1. Field of the Invention
This invention relates to a method of dosing and administering IGF-I in an intermittent fashion such that the maximum favorable biological activity of IGF-I is achieved and maintained in the treatment of chronic disorders, with minimized unfavorable side effects.
2. Description of Related Disclosures
Human insulin-like growth factor-I (IGF-I) is a 7649-dalton polypeptide with a pI of 8.4 [Rinderknecht and Humbel, Proc. Natl. Acad. Sci. USA, 73:2365 (1976); Rinderknecht and Humbel, J. Biol. Chem., 253: 2769 (1978)] belonging to a family of somatomedins with insulin-like and mitogenic biological activities that modulate the action of growth hormone (GH). Van Wyk et al., Recent Prog. Horm. Res., 30: 259 (1974); Binoux, Ann. Endocrinol., 41: 157 (1980); Clemmons and Van Wyk, Handbook Exp. Pharmacol., 57: 161 (1981); Baxter, Adv. Clin. Chem., 25:49 (1986); U.S. Pat. No. 4,988,675; WO 91/03253; and WO 93/23071. IGF-I has hypoglycemic effects similar to insulin but also promotes positive nitrogen balance. Underwood et al., Hormone Res., 24: 166 (1986); Guler et al., N. Engl. J. Med., 317: 137 (1987). Due to this range of activities, IGF-I is being tested in humans for uses ranging from wound healing to the reversal of whole body catabolic states to treatment of heart conditions such as congestive heart failure. Guler et al., Proc. Natl. Acad. Sci. USA, 8-5:4889 (1988); Duerr et al., J. Clin. Invest., 95: 619-627 (1995). IGF-I is also being tested in the clinic for treating diabetes.
U.S. Pat. Nos. 5,273,961; 5,126,324; 5,187,151; 5,202,119; 5,374,620; 5,106,832; 4,988,675; 5,106,832; 5,068,224; 5,093,317; and 4,876,242 and WO 92/11865 and WO 94/16722 disclose various methods of treating patients using IGF-I.
A general scheme for the etiology of some clinical phenotypes which give rise to insulin resistance and the possible effects of administration of IGF-I on selected representative subjects is given in several references. See, e.g., Elahi et al., "Hemodynamic and metabolic responses to human insulin-like growth factor-1 (IGF-1) men," in Modern Concepts of Insulin-Like Growth Factors, (Spencer, EM, ed.), Elsevier, N.Y., pp. 219-224 (1991); Quinn et al., N. Engl. J. Med., 323:1425-1426 (1990); Schalch et al., "Short-term metabolic effects of recombinant human insulin-like growth factor 1 (rhIGF-1) in type 11 diabetes mellitus," in: Modern Concepts of Insulin-Like Growth Factors, (Spencer, EM, ed.), Elsevier, N.Y., pp. 705-714 (1991); Schoenle et al., Diabetolgia, 34:675-679 (1991); Usala et al., N. Engl. J. Med., 327:853-857 (1992) ; Lieberman et al., J. Clin. Endo. Metab., 75:30-36 (1992); Zenobi et al., J. Clin. Invest, 90: 2234-2241 (1992); Zenobi et al., J. Clin. Invest., 89:1908-1913 (1992); Kerr et al., J. Clin. Invest., 91: 141-147 (1993); and U.S. Pat. No. 4,988,675. WO 94/16722 discloses a method of chronic modification of cell barrier properties by exposing a cell to a modification-effective amount of IGF-I for at least about seven days and a method of chronic amelioration or reversal of insulin resistance. However, when IGF-I was used to treat type II diabetes patients in the clinic at a dose of 120-160 .mu.g/kg twice daily, the side effects outweighed the benefit of the treatment. Jabri et al., Diabetes, 43: 369-374 (1994). See also Wilton, Acta Paediatr., 383: 137-141 (1992) regarding side effects observed upon treatment of patients with IGF-I.
IGF-I has also been found to exert a variety of actions in the kidney. Hammerman and Miller, Am. J. Physiol., 265: F1-F14 (1993). It has been recognized for decades that the increase in kidney size observed in patients with acromegaly is accompanied by a significant enhancement of glomerular filtration rate. O'Shea and Layish, J. Am. Soc. Nephrol., 3:157-161 (1992). U.S. Pat. No. 5,273,961 discloses a method for prophylactic treatment of mammals an risk for acute renal failure. Infusion of the peptide in humans with normal renal function increases glomerular filtration rate and renal plasma flow. Guler et al., Acta Endocrinol., 121:101-106 (1989); Guler et al., Proc. Natl. Acad. Sci. USA, 6:2868-2872 (1989); Hirschberg et al., Kidney Int., 43:387-397 (1993); U.S. Pat. No. 5,106,832. Further, humans with moderately reduced renal function respond to short-term (four days) IGF-I administration by increasing their rates of glomerular filtration and renal plasma flow. Hence, IGF-I is a potential therapeutic agent in the setting of chronic renal failure. O'Shea et al., Am. J. Physiol., 264: F917-F922(1993).
Additionally, renal function can be enhanced over a period of days by the administration of IGF-I in the setting of end-stage chronic renal failure. This is important, since end-stage chronic renal failure is a condition that can only be treated with dialysis or transplantation and the incidence thereof is rapidly increasing. Diabetics and the elderly tend to have this condition. Approximately sixty percent of patients with end-stage chronic renal failure are on hemodialysis, about ten percent are on peritoneal dialysis, and the remaining about thirty percent receive a transplant. Dialysis therapy is initiated in over 50,000 patients each year in the United States. An additional 25% of patients who have reached end-stage renal failure are denied access to dialysis each year. The cost of caring for these patients on dialysis currently averages over $200 million a month. Furthermore, the patients exhibit an impaired lifestyle on dialysis. Despite the fact that IGF-I can enhance renal function for those experiencing end-stage chronic renal failure, the enhancements of the glomerular filtration rate and renal plasma flow induced by IGF-I short-term do not persist during long-term administration and incidence of side-effects is high. Miller et al., Kidney International, 46:201-207 (1994).
The dynamics of IGF-I interaction with sensitive tissues are complex and incompletely understood. Biological activity of circulating IGF-I is regulated by levels of plasma IGFBPs, which both enhance and inhibit IGF-I actions. Cohick and Clemmons, Annu. Rev. Physiol., 55:131-153 (1993); Kupfer et al., J. Clin. Invest., 91:391-396 (1993). In addition, IGFBPs present in tissues regulate the interaction of circulating IGF-I with its receptor. Tissue IGF-I receptor density is altered by changes in levels of circulating IGF-I. In kidney, the numbers of IGF-I receptors are inversely related to levels of circulating IGF-I. Hise et al., Clin. Sci., 83: 223-239 (1991).
It is known that under some circumstances elevated levels of circulating IGF-I are associated with or directly causative of long-term changes in renal function. For example, the enhancements of inulin and PAH clearances that accompany the elevations of circulating GH and IGF-I in patients with acromegaly are sustained over years of time. Ikkos et al., Acta Endocrinol., 21: 226-236 (1956). An increase in creatinine clearance occurred within the first 12 days of IGF-I administration to a GH-insensitive Laron dwarf. The increase was progressive over the next 59 days. Walker et al., J. Pediatr., 121: 641-646 (1992).
GH stimulates the synthesis of IGFBP3 in liver. Hammerman and Miller, supra; Cohick and Clemmons, supra; Kupfer et al., supra. It is the reduction in levels of circulating GH resulting from IGF-I inhibition of pituitary GH release that is thought to result in the fall of circulating IGFBP3 in humans administered IGF-I. Because of their GH insensitivity, IGFBP3 levels are low and are increased by IGF-I in Laron dwarfs. Kenety et al., Acta Endocrinol., 128:144-149 (1993). This difference or another in the IGF-I effector system could explain the absence of refractoriness to IGF-I in these individuals.
Walker et al., supra, found that IGF-I increased urinary calcium excretion or urinary volume. Miller et al., supra, did not see such effect. IGF-I also enhances the transport of phosphate across the proximal tubular brush border membrane. Quigley and Baum,J. Clin. Invest., 88:368-374 (1991). Patients with long-standing acromegaly showed marked renal hypertrophy and had supranormal glomerular filtration rates, suggesting that the hyperfiltration that accompanies long-standing elevations of circulating GH and IGF-I in humans is not injurious to the kidney. Ikkos et al., supra; Hoogenberg et al., Acta Endocrinol., 129:151-157 (1993).
For complete reviews of the effect of IGF-I on the kidney, see, e.g., Hammerman and Miller, Am. J. Physiol., 265: F1-F14 (1993) and Hammerman and Miller, J. Am. Soc. Nephrol., 5:1-11 (1994) .
As to anabolic indications for IGF-I, in HIV-infected patients treated consecutively with IGF-I, the IGF-I promoted anabolism but tachyphylaxis developed rapidly in the patients. Lieberman et al., U.S. Endocrine Meeting, June 1993 (Abst. 1664), disclosed more fully by Lieberman et al., J. Clin. Endo. Metab., 78:404-410 (1994). In patients with severe head injuries, a condition associated with profound hypercatabolism and nitrogen loss, infusion of IGF-I produced only a transient positive nitrogen balance. In the first week the patients experienced a positive nitrogen balance, but during the second week, a negative nitrogen balance developed. Chen et al., U.S. Endocrine Meeting, June 1993 (Abst. 1596).
All of these studies indicate that there is a need in the art for a treatment with IGF-I that does not subside after a certain period of treatment time and one that both maximizes efficacy and minimizes the side effects of IGF-I.